Author: Bui, Thai ; Peña, Adrian ; Lent, Brianna ; Jacobson, Kenneth A. ; Chou, Kerry ; Gao, Zhan-Guo ; Appel, Taylor L. ; Streicher, John M. ; Keresztes, Attila ; Hecksel, Ryan ; Schwarz, Abigail M. ; Seekins, Caleb A. ; Al-Obeidi, Fahad A. ; Gamez-Rivera, Martín

AbstractTerpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa. A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord–specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A2AR agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.

01 Sep 2024·Molecular Neurobiology

Correction: Anandamide and WIN 55212–2 Afford Protection in Rat Brain Mitochondria in a Toxic Model Induced by 3-Nitropropionic Acid: an In Vitro Study

Author: Olivera-Pérez, Carolina I ; Maya-López, Marisol ; Monsalvo-Maraver, Luis Angel ; Santamaría, Abel ; Medina-Campos, Omar ; Delgado-Arzate, Ana Laura ; El-Hafidi, Mohammed ; Silva-Palacios, Alejandro ; Túnez, Isaac ; Tinkov, Alexey A ; Aschner, Michael ; Pedraza-Chaverri, José ; Zazueta, Cecilia ; Retana-Márquez, Socorro

01 Sep 2024·Molecular Neurobiology

Anandamide and WIN 55212–2 Afford Protection in Rat Brain Mitochondria in a Toxic Model Induced by 3-Nitropropionic Acid: an In Vitro Study

Article

Author: Olivera-Pérez, Carolina I ; Maya-López, Marisol ; Monsalvo-Maraver, Luis Angel ; Santamaría, Abel ; Delgado-Arzate, Ana Laura ; Medina-Campos, Omar ; El-Hafidi, Mohammed ; Silva-Palacios, Alejandro ; Túnez, Isaac ; Tinkov, Alexey A ; Aschner, Michael ; Pedraza-Chaverri, José ; Zazueta, Cecilia ; Retana-Márquez, Socorro

AbstractMitochondrial dysfunction plays a key role in the development of neurodegenerative disorders. In contrast, the regulation of the endocannabinoid system has been shown to promote neuroprotection in different neurotoxic paradigms. The existence of an active form of the cannabinoid receptor 1 (CB1R) in mitochondrial membranes (mitCB1R), which might exert its effects through the same signaling mechanisms as the cell membrane CB1R, has been shown to regulate mitochondrial activity. Although there is evidence suggesting that some cannabinoids may induce protective effects on isolated mitochondria, substantial evidence on the role of cannabinoids in mitochondria remains to be explored. In this work, we developed a toxic model of mitochondrial dysfunction induced by exposure of brain mitochondria to the succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP). Mitochondria were also pre-incubated with the endogenous agonist anandamide (AEA) and the synthetic CB1R agonist WIN 55212–2 to evaluate their protective effects. Mitochondrial reduction capacity, reactive oxygen species (ROS) formation, and mitochondrial swelling were assessed as toxic markers. While 3-NP decreased the mitochondrial reduction capacity and augmented mitochondrial ROS formation and swelling, both AEA and WIN 55212–2 ameliorated these toxic effects. To explore the possible involvement of mitCB1R activation on the protective effects of AEA and WIN 55212–2, mitochondria were also pre-incubated in the presence of the selective CB1R antagonist AM281, which completely reverted the protective effects of the cannabinoids to levels similar to those evoked by 3-NP. These results show partial protective effects of cannabinoids, suggesting that mitCB1R activation may be involved in the recovery of compromised mitochondrial activity, related to reduction of ROS formation and further prevention of mitochondrial swelling.

100 Deals associated with WIN-552122

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Preclinical	US	University of Minnesota	-
Glaucoma	Preclinical	US	Sanofi Winthrop LP	-
Movement Disorders	Preclinical	US	University of Minnesota	-
Nervous System Diseases	Preclinical	ES	-	-
Pain	Preclinical	US	University of Minnesota	-
Pain	Preclinical	US	Sanofi Winthrop LP	-
Movement Disorders	Discovery	US	Sanofi Winthrop LP	-

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